The present invention relates to 4,5-dihydroisoxazolylalkylpiperazine derivatives having selective biological activity at dopamine D3 or D4 receptors represented by the following formula (1), and its preparation method through reductive amination reaction in the presence of a reducing agent, 
wherein R1 represents aryl, arylalkyl, diarylalkyl, and heteroaryl, where the aryl groups may have one or more substituents selected from C1-C6 alkyl, C1-C6 alkoxy and a halogen atom, for example, phenylmethyl, diphenylmethyl, (2-trifluoromethylphenyl)methyl, phenyl, 2-methylphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 2-ethoxyphenyl, 2-fluorophenyl, 4-fluorophenyl, 2-chlorophenyl, 4-chlorophenyl, 2-pyrimidyl, 4-chlorobenzhydryl, or 4,4xe2x80x2-difluorobenzhydryl group;
R2 represents aryl, arylalkenyl and heteroaryl group, where the aryl groups may have one or more substituents selected from a halogen atom, nitro, C1-C6 alkyl and C1-C6 alkoxy group, for example, phenyl, 4-fluorophenyl, 4-chlorophenyl, 3-nitrophenyl, 2,4-dimethoxyphenyl, 3,4-dimethoxyphenyl, 3-phenoxyphenyl, styryl, 2-thienyl or 2-thiazol group
X represents CH or a nitrogen atom; and
n represents 3 or 4.
Dopamine is a neurotransmitter found in the brain of animals including human, which is indispensable in the transmission of nerve signals. The dopamine antagonist inhibits the binding of dopamine and dopamine receptor as an antipsychotic, and it is used for the treatment of mental disorder like schizophrenia.
According to recent publications, there are more than one type of dopamine receptors that function through G-protein, and some dopamine antagonists inhibit one type of dopamine receptor preferentially to the others. As the representative dopamine receptors early found, there are D1 receptor that induces the activation of adenylyl cyclase and D2 receptor that inhibits it. Afterwards totally 5 dopamine receptors were found, and they have been classified into two groups: D1 group (D1 and D5) and D2 group (D2, D3 and D4).
Mental disease is related with central dopaminergic nerve system, and central postsynaptic receptor antagonists or presynaptic receptor (autoreceptor) agonists can be used as antipsychotics. Especially the D2 group receptor antagonist haloperidol, a typical antipsychotic, gives extrapyramidal side effect (EPS) in case of long-term treatment. Such side effects occur from hypersensitive reaction due to the long-term inhibition of central dopamine receptor, and include involuntary movement (tardive dyskinesia) and hyperprolactinaemia caused by the inhibition of dopamine receptor at the pituitary gland. On the other hand, the antagonists that selectively act on dopamine D3 or D4 receptors are known to have no side effects like extrapyramidal side effect and tardive dyskinesia.
Accordingly, in the treatment of mental disease like schizophrenia, development of drugs having few side effects, i.e. new compounds that selectively acts on dopamine D3 or D4 receptor is of great importance.
As a result of the efforts to develop novel chemical compounds that selectively act on dopamine D3 or D4 receptors, the inventors found that novel compounds obtained by introducing various substituents to 4,5-dihydroisoxazolylalkylpiperazine skeleton have superior and selective antagonistic activity against dopamine D3 or D4 receptors.
Accordingly, the present invention aims at providing novel compounds useful for the treatment of mental disease, preparation methods thereof and pharmaceutical compositions containing them respectively as effective components.